Centella asiatica effects on neuroinflammatory responses in Drosophila models of acute inflammation and aging

项目总结 衰老的特征是免疫功能失调，导致生物韧性下降和 增加了对死亡的脆弱性。上了年纪的人会出现炎症，这种状态的特征是 炎性细胞因子水平，这有助于增加慢性发病率、虚弱和导致 老年人神经和功能恢复力的退化。没有批准的干预措施 目前可用于中和发炎的有害影响。某些生活方式的改变，如 有规律的体力活动、限制卡路里摄入和植物性饮食会降低体内的 慢性炎症导致生物衰老减慢。目前，许多植物性膳食补充剂 市场上有声称可以提高对与年龄相关的认知、睡眠或情绪恶化的适应能力的产品。 然而，大多数这些制剂的分子作用机制仍不清楚。本弗雷拉 OHSU植物膳食补充剂研究中心参与了对 印度阿育吠陀植物积雪草在缓解与年龄相关的神经变化中的作用。这项研究 在该中心进行的研究表明，热水狗尾草提取物(CAW)对 体外和体内临床前期小鼠的抗氧化反应、线粒体活性和突触健康 模特们。然而，BENFRA中心之前的研究还没有评估标准化的潜力 CAW提取物可减少体内衰老模型或急性神经炎模型中的脑特异性炎症。 在这项应用中，我们建议测试CAW改善急性和年龄相关疾病的能力 遗传易驯化的生物黑腹果蝇的神经炎症。与哺乳动物相似， 果蝇促炎分子的转录是由进化上保守的 转录因子NF-κB，其活性也随着年龄的增长而增加。在这里，我们将评估CAW对以下方面的影响 天然免疫系统活跃的果蝇中衰老野生型果蝇的神经炎症 在经历加速衰老的果蝇模型中，百草枯(PQ)诱导的氧化应激。在每一个中 模型中，使用优化的CAW喂养方案，我们将评估存活率、脑特异性炎症水平 基因表达或氧化应激标志物。此外，我们将测试CAW对神经学结果的影响 通过测量脑组织的活动行为和空泡神经病理。这项研究将验证 CAW可降低急性神经炎症和衰老体内模型的炎症水平，如果它能改善 相关的神经学表型。CAW可以影响炎症的演示将作为基础 将炎症生物标记物作为未来CAW临床试验的重要终点。

PROJECT SUMMARY Aging is characterized with dysregulated immune function contributing to the decline in biological resilience and increasing vulnerability to death. Aging individuals develop inflammaging, a state characterized by elevated levels of inflammatory cytokines, which contribute to the increase in chronic morbidity, frailty and lead to deterioration of neurological and functional resilience in the elderly. There are no approved interventions currently available to counteract the deleterious effects of inflammaging. Certain lifestyle modifications such as regular physical activity, calorie restriction and plant-based diet have been associated with decreased levels of chronic inflammation resulting in slowed biological aging. Numerous botanical dietary supplements are currently available on the market with claims to improve resilience to age-related deterioration in cognition, sleep or mood. However, the molecular mechanism of action for most of these formulations remains unknown. The BENFRA Botanical Dietary Supplements Research Center at OHSU has been involved in evaluating the potential of the Ayurvedic plant Centella asiatica (gotu kola) in alleviating age-related neurological changes. The research performed at the center has demonstrated that hot water gotu kola extract (CAW) has positive effects on antioxidant response, mitochondrial activity and synaptic health in both in vitro and in vivo preclinical mouse models. However, the previous research at the BENFRA center has not assessed the potential of standardized CAW extract to reduce brain specific inflammation in in vivo models of aging or acute neuroinflammation. In this application we propose to test the ability of CAW to ameliorate acute and age-related neuroinflammation in the genetically tractable organism Drosophila melanogaster. Similar to mammals, transcription of pro-inflammatory molecules in Drosophila is mediated by the evolutionarily conserved transcription factor NF-κB, whose activity also increases with age. Here, we will evaluate the effects of CAW on neuroinflammation in aging wild type Drosophila, in Drosophila with constitutively active innate immune system undergoing accelerated aging, and in a Drosophila model of Paraquat (PQ)-induced oxidative stress. In each model, using optimized CAW feeding regimens, we will assess survival, the levels of brain-specific inflammatory gene expression or oxidative stress markers. Moreover, we will test the effects of CAW on neurological outcomes by measuring mobility behavior and vacuolar neuropathology in brain tissue. This research will verify whether CAW lowers levels of inflammation in in vivo models of acute neuroinflammation and aging, and if it ameliorates associated neurological phenotypes. A demonstration that CAW can affect inflammaging will serve as the basis of including biomarkers of inflammation as important endpoints in future clinical trials of CAW.